This invention relates to novel processes for producing cyanobenzoic acid derivative compounds, salts thereof and intermediates therefor. The invention further relates to improved catalytic processes for making carboxylic acid derivatives from substituents on an unsaturated aryl compound.
Known processes exist for making cyanobenzoic acid compounds, particularly 4-cyanobenzoic acid (CAS 619-65-8) and 2-fluoro-4-cyanobenzoic acid (benzoic acid 119, for example, in reaction Scheme 17 of U.S. Pat. No. 5,731,324, at pages 77-80) compounds from the corresponding 4-aminotoluene and 4-amino-2-fluorotoluene compounds. However, the starting materials for such process are often very expensive, have limited availability, and may be difficult to modify in a good yield. For example, 2-fluoro-4-cyanobenzoic acid can be prepared from 4-amino-2-fluoro-toluene using standard methods in the presence of EDCI and DMAP, or the like. Often the yield for making derivatives, or the recovery of intermediates are difficult with respect to nitrites. Oxidation procedures to convert the methyl group of the toluene to a carboxylic acid group when the nitrile group is present on the aromatic ring often tend to have a relatively low yield and sometimes a complicated recovery and purification. When the presence of both a carboxylic acid group and the halogen group are desired on the ring, the procedures become even more difficult and the low yields are very common, which are not well tolerated. The yield is also complicated by the fact that the starting materials are also expensive. Therefore, there is a need for efficient processes to produce p- and m-cyanobenzoic acid derivatives (and the like with pyridyl derivatives) which are particularly substituted ortho to the carboxylic acid group with selected substituents, such as halogens, alcohols or ethers, which use economically priced starting materials and higher yielding overall steps than current processes, wherein the processes can be scaled to industrial levels with readily available materials and reagents. Such compounds, their intermediates and salts are useful as functional groups in a wide variety of industrial and pharmaceutical fields.
The present invention relates to novel processes for producing para or meta cyanobenzoic acid derivative compounds wherein up to four of the free hydrogens on the benzene ring may be replaced with a group such as I, F, Br, Cl, OH, O-alkyl and the like. Further, the process according to the invention provides processes for making the corresponding carboxyl substituted pyridyl compounds having a cyano group located ortho or meta with respect to the carboxyl group. Such functional group substituted phenyl and pyridyl compounds are intermediates for producing therapeutic agents, for example, for disease states in mammals that have disorders caused by or impacted by platelet dependent narrowing of the blood supply.
In accordance with one aspect of the present invention, there is provided a process for preparing derivatives of 4-cyanobenzoic acid. The process comprises contacting 2-amino-4-nitrotoluene with HR/NaNO3 followed by heating to form 2-R-substituted 4-nitrotoluene: 
wherein R is hydrogen, alkyl, halo, or alkoxy, followed by exposing the above compound to reducing conditions to reduce the nitro group on the ring to form a 2-R-substituted 4-aminotoluene, contacting the reduced compound with NaNO2/HCl followed by the addition of a source of cyanate ion to form 2-R-substituted 4-cyanotoluene, and oxidizing the methyl group of the cyano compound to form 2-R-substituted-4-cyanobenzoic acid.
In accordance with a further aspect of the present invention, there is provided an alternate method for preparing derivatives of 4-cyanobenzoic acid. The process comprises contacting 2-amino-4-nitrotoluene with HR/NaNO3 followed by heating to form 2-R-substituted 4-nitrotoluene: 
wherein R is hydrogen, alkyl, halo, or alkoxy, followed by exposing the above compound to oxidizing conditions to oxidize the methyl group on the ring to form 2-R-substituted 4-nitrobenzoic acid, hydrogenating the nitro group on the ring to form 2-R-substituted 4-aminobenzoic acid, and contacting the 2-R-substituted 4-aminobenzoic acid with NaNO2/HCl followed by the addition of a source of cyanate ion to form a 2-R-substituted 4-cyanobenzoic acid derivative compound.
In accordance with another aspect of the present invention, there is provided a process for preparing derivatives of 3-cyanobenzoic acid. The process comprises contacting 2-amino-5-nitrotoluene with HR/NaNO3 followed by heating to form 5-R-substituted 3-nitrotoluene: 
wherein R is hydrogen, alkyl, halo, or alkoxy, followed by hydrogenating the nitro group on the above compound to form 5-R-substituted 3-aminotoluene, contacting the 5-R-substituted 3-aminotoluene with NaNO2/HCl followed by the addition of a source of cyanate ion to form 5-R-substituted 3-cyanotoluene, and oxidizing the methyl group on the ring to form 5-R-substituted 3-cyanobenzoic acid.
In accordance with a further aspect of the present invention, there is provided an alternate process for preparing derivatives of 3-cyanobenzoic acid. The process comprises contacting 2-amino-5-nitrotoluene with HR/NaNO3 followed by heating to form 5-R-substituted 3-nitrotoluene: 
wherein R is hydrogen, alkyl, halo, or alkoxy, followed by oxidizing the methyl group on the ring to form 5-R-substituted 3-nitrobenzoic acid, hydrogenating the nitro group on the ring to form 5-R-substituted 3-aminobenzoic acid, and contacting the 5-R-substituted 3-aminobenzoic acid with NaNO2/HCl followed by the addition of a source of cyanate ion to form 5-R-substituted 3-cyanobenzoic acid.
In accordance with yet another aspect of the present invention, there is provided a process for preparing 3-fluoro-4-cyanobenzoic acid. The process comprises contacting 2-chloro-4-nitrobenzoic acid with a metal fluoride to cause a halogen exchange to form 2-fluoro-4-nitrobenzoic acid; exposing the 2-fluoro-4-nitrobenzoic acid to reducing conditions to reduce the nitro group on the ring to form 2-fluoro-4-aminobenzoic acid; and contacting the 2-fluoro-4-aminobenzoic acid with NaNO2/HCl followed by the addition of a source of cyanate ion to form 3-fluoro-4-cyanobenzoic acid.